Cocaine is a habit-forming stimulant that produces "reinforcing" effects. Central dopamine has been hypothesized to play a major role in the expression of pharmacological effects of cocaine, but direct biochemical support for this view is sparse and inconsistent. The latter may be due to two important factors: Most information on the biochemical effects of cocaine has come from acute studies, and the striatum and nucleus accumbens have been the brain regions most frequently analyzed. Therefore, certain important brain regions may have been overlooked. We have systematically evaluated the effects of 1 to 3 weeks chronic cocaine administration on central and peripheral biogenic amines, in particular, the catecholamines. Results revealed a preferential, long-term reduction of dopamine turnover and/or metabolism in both the periphery and the brain. The frontal cortex and the hypothalamus apparently are the areas most affected. We have concentrated our efforts on understanding the mechanism by which cocaine reduces frontal cortex DA production and metabolism. A careful search for 6-hydroxydopamine (6-OHDA) in the frontal cortex and striatum with gas chromatography/mass spectrometry revealed no endogenous 6-OHDA in these brain regions. Administration of high doses of cocaine, methamphetamine and dopamine-releasing agents failed to produce detectable concentrations of 6-OHDA in the brain. A substance with a retention time close to 6-OHDA was occasionally detected, and may be the substance found by HPLC in the striata of rats given high doses of amphetamine. We hope to identify this substance and follow its origin and metabolic fate by using a triple quadrupole mass spectrometer.